ABSTRACT: PROJECT 3: CARDIOVASCULAR RISK IN WOMEN WITH HIV Although heightened cardiovascular disease (CVD) risk in HIV is partly attributable to an increased burden of CVD traditional risk factors and to antiretroviral therapy-mediated effects, persistent inflammation and immune dysregulation may also play a role. Women have a greater burden of CVD risk factors, including inflammation, despite having less obstructive coronary artery disease (CAD), but nevertheless have worsening clinical outcomes. Among HIV+ women, CVD risk is further compounded by estrogen deficiency and early menopause. Coronary computed tomographic angiography (CCTA) can not only detect the presence and volume of plaque, but assess high risk plaque (HRP) characteristics. Vascular functional and structural measures including carotid intima-media thickness (CIMT), carotid plaque, and brachial artery endothelial function are predictive of future MI and stroke. In HIV+ subjects, CIMT is thicker and carotid plaque 1.5-fold more prevalent compared to controls. Magnetic resonance imaging (MRI) of the carotid arteries provides a state-of-the-art, accurate and reproducible measure of carotid arterial wall thickness, plaque and its high risk characteristics, and permits reliable measures of disease progression. Circulating bone marrow-derived progenitor cells (PCs) are actively involved in cardiovascular homeostasis and mediate cardiovascular repair and regeneration. We have shown that a reduction in the number and migratory activity of PCs is higher CVD risk and mortality. Moreover, women have lower numbers of circulating PCs compared to men, and levels of PCs correlate with estrogen status. In HIV+ subjects, PC counts are lower providing evidence for reduced regenerative capacity. Our overall objective in this Project is to define the contribution of HIV infection in women to both injurious factors (inflammation, HIV status) and to endogenous reparative/regenerative processes in the setting of estrogen deficiency and their combined impact on the presence and progression of sub-clinical coronary and carotid artery atherosclerosis measured using CCTA and carotid MRI. In Aim 1, we will study the impact of HIV-related changes in regenerative capacity, endothelial function and arterial stiffness on prevalent coronary and carotid arterial disease. In Aim 2, we propose to assess the factors that underlie the progression of carotid arterial disease, measured using serial MRI over a 2-year period. In Aim 3, we will compare the extent of total atherosclerotic plaque volume and its' high risk characteristics, measured using CCTA in women with and without HIV.